GP134 Confirmation of pathogenetic heterogeneity of diabetes mellitus in children using whole-exome sequencing

Background In the conditions of dynamic development diagnostic capabilities and understanding of the pathogenetic mechanisms of diabetes, the main task of clinicians is the earliest possible verification of the type of diabetes. New diagnostic methods such as whole-exome sequencing allow to finally verify the type of diabetes mellitus and are of special interest. Aim Determine the frequency of occurrence and molecular-genetic characteristics of monogenic diabetes in children - residents of St.Petersburg. Methods We examined 99 patients with suspected hereditary variants of diabetes: MODY, diabetes as a part of genetic syndromes and diabetes occurrence before 6 month.All patients have chronic hyperglycemia, detectable of C-peptide level, negative autoimmune markers for diabetes type 1 (except IPEX-syndrom) and absence of signs of metabolic syndrome for older children. In our study of DNA of patients with suspicion of monogenic diabetes was performed by whole-exome sequencing. Genetic variants were screened in a total of 35 genes: 13 genes causative of MODY (HNF4A(MODY1), GCK(MODY2), HNF1A(MODY3), PDX1(MODY4), HNF1B(MODY5), NEUROD1(MODY6), KLF11(MODY7), CEL(MODY8), PAX4(MODY9), INS(MODY10), BLK(MODY11), ABCC8(MODY12), KCNJ11(MODY13), and 22 genes causative of transient or permanent neonatal diabetes, including the ones related to specific syndromes (EIF2AK3, RFX6, WFS1, ZFP57, FOXP3, AKT2, PPARG, APPL1,PTF1A, GATA4, GATA6, GLIS3, IER3IP1, LMNA, NEUROG3, PAX6, PLAGL1, SLC19A2, SLC2A2, SH2B1, SERPINB4, MADD). Results Overall, 53 out of 99 patients (53.5%) had genetic variants in the target genes. The most common mutations in the group of patients with MODY were mutations in the GCK gene – 80% (n=36), HNF1A 13.3% (n=6), WFS1 4.4% (n=2), PAX4 = 2.2% (n=1). In cases of neonatal diabetes, including genetic syndromes with diabetes, significant mutations were detected in 8 of 18 patients. Thanks to the possibility to performed whole-exome sequencing, we managed to identify and genetically confirm rare syndromic forms of diabetes, such as: diabetes in the structure of Wolcott–Rallison syndrome (mutation in the EIF2AK3 gene) (n=1), diabetes in the structure of IPEX syndrome (n=1), as well as diabetes due to a mutation in the GATA6 gene (n=1) and a biallelic mutation in the SLC19A2 gene (n=1). Conclusions Using basic differential diagnostic criteria to establish monogenic diabetes, the molecular genetic confirmation of the diagnosis among suspected patients amounts to 53%. Higher mutation detection rate may be achieved by increasing number of genes tested. One more advantage of whole-exome sequencing should be mentioned: DNA sequencing data may be easily stored for further analysis of newly discovered candidate genes.